Programmed cell death, or apoptosis, is important for the development of most organs also for adult tissue homeostasis and remodeling. However, an inexorable loss of terminally differentiated heart muscle cells is a pivotal causal factor for the development of heart failure, the current leading cause of death in developed countries and the predicted number one killer worldwide by 2020, but heart failure currently lacks effective therapies. Thus, identifying genetic modifiers and molecular mechanisms governing heart muscle cell apoptosis has been a major focus in cardiovascular biology and medicine in order to reveal new etiological insights and therapeutic targets for the devastating cardiovascular disease. WE have recently identified a novel endogenous Ras inhibitor, hyperplasia suppressor gene (HSG), also named rat mitofusin-2 (rMfn-2) after its human homologue mitofusin-2 (Mfn-2). Although previous studies have shown that human Mfn-2 and its homologues localize to the mitochondrial outer membrane and play an essential role in mitochondrial fusion, we have demonstrated that HSG exhibits profound anti-proliferative effects in vivo and in vitro via inhibiting the Ras-ERK/MAPK signaling pathway, and that downregulation of rHSG contributes to various vascular proliferative disorders. Here, we demonstrate that HSG (also named mitofusin-2), a mitochondria protein, is an important determinant of heart muscle cell apoptosis. Endogenous HSG expression is profoundly upregulated during myocardial ischemia in vivo or oxidative stress in cultured rat cardiomyocytes, and causes cardiomyocyte apoptosis when overexpressed, as manifested by increased mitochondrial cytochrome c release and activation of caspase-9 and caspase-3. The pro-apoptotic effect of HSG is mediated by inhibiting of PI3K/Akt cell survival signal, since excessive HSG inhibits both basal and serum-induced activation of Akt. Remarkably, expression of a constitutively active mutant PI3K prevents HSG-induced apoptosis, and siRNA-mediated gene knockdown of HSG effectively protects cells against oxidative stress-induced apoptosis. These findings marks HSG as a crucial mediator of clinically important ischemia/oxidative stress-induced heart disease, and suggest gene knockdown or inhibition of HSG function might provide a highly effective novel therapy in treating the devastating disease, heart failure, that currently lacks effective therapies.